Experimental and clinical evidence suggest that in severe post traumatic and septic states abnormalities of energy metabolism, inclPding excess proteolysis, may be based upon a fuel deficit in insulin resistant skeletal muscle. Whereas, severe sepsis in the presence of the usual high cardiac output is associated with elevated fasting blood insulin levels, in the low output shock state blood insulin is markedly reduced. In vitro measurements indicate that enzyme activities of energy pathways in skeletal muscle do not respond normally to insulin stimulation in the presence of sepsis. Liver and adipose tissue appear to respond normally in this respect. During the coming year three approached will be continued to complete these studies. In vivo measurement of hepatic blood flow and substrate utilization in pigs will compare hepatic metabolism in starvation and in the high or low output circulatory states after induction of peritonitis. Under these same conditions similar observations on myocardial metabolism using recently developed techniques will relate energy production to stroke work. An attempt will be made to find an explanation for the prompt relief of myocardial failure in the low output state by administration of glucose, potassium, and insulin. Finally, to test the hypothesis that the insulin resistance of skeletal muscle and other metabolic abnormalities of major trauma and infection are in part caused by circulating agents, possibly vasoactive peptides, the metabolic effects on tissues of plasma fractions of plasma from septic and normal animals or patients will be compared both in vivo and in vitro.